Affinage

MAP3K11

Mitogen-activated protein kinase kinase kinase 11 · UniProt Q16584

Length
847 aa
Mass
92.7 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP3K11 (MLK3) is a mixed-lineage serine/threonine MAP3K that serves as a signal-integrating node funneling stress, cytokine, and small-GTPase inputs into MAPK cascades governing cell migration, proliferation, and survival (PMID:9003778, PMID:8702571, PMID:8195146, PMID:8183572, PMID:8108137). Its modular architecture—an SH3 domain, a kinase domain with mixed-lineage homology, tandem leucine/isoleucine zippers, a Cdc42/Rac-binding CRIB motif, and a proline-rich C-terminus—supports autophosphorylation on serine and threonine that requires an intact ATP-binding site (PMID:8195146, PMID:8183572, PMID:8108137). Activation is GTPase-coupled: Cdc42 engages the CRIB motif to alter MLK3 phosphorylation and drive leucine-zipper-mediated disulfide-bridged homodimerization, and this oligomerization is specifically required for productive phosphorylation of the activating Thr258 of MKK4 and downstream JNK activation (PMID:9829970, PMID:10799501, PMID:10862766). Once active, MLK3 directly phosphorylates and activates SEK1/MKK4 and MKK3/6 to selectively turn on the SAPK/JNK and p38 pathways (PMID:9003778, PMID:8702571), and is additionally required for B-Raf phosphorylation at Thr598/Ser601 to drive ERK signaling and serum-stimulated proliferation (PMID:15258589, PMID:15467451). MLK3 is activated by ceramide and by TNF-α through direct binding to TRAF2, with genetic ablation revealing a selective requirement for the TNF→JNK axis (PMID:12504027, PMID:15831472, PMID:19918265). Its kinase activity is restrained by AKT-mediated phosphorylation at Ser674, a brake exploited by estrogen-/HER2-driven signaling in breast cancer to suppress pro-apoptotic MLK3-JNK output (PMID:20145118, PMID:26152725). Beyond catalysis, MLK3 acts as a kinase-independent scaffold that binds p63RhoGEF to limit Rho activation and, together with JNK-dependent paxillin phosphorylation and FRA-1/MMP-1/MMP-9 upregulation, drives focal-adhesion turnover, invasion, and metastasis (PMID:18851832, PMID:22700880, PMID:28604765). MLK3 also localizes near centrosomes and promotes microtubule instability at mitotic entry (PMID:12529434), and in vivo it controls CDC42-dependent osteoblast differentiation and skeletal mineralization, with Mlk3−/− mice modeling Aarskog-syndrome-like skeletal defects (PMID:21965325).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1994 High

    Established MLK3 as a multidomain serine/threonine kinase, defining the structural toolkit (SH3, kinase, leucine zippers, CRIB, proline-rich region) through which it would later integrate signals.

    Evidence cDNA cloning, domain analysis, and ATP-site mutagenesis confirming autophosphorylation

    PMID:8108137 PMID:8183572 PMID:8195146

    Open questions at the time
    • Did not identify physiological substrates or upstream activators
    • No structural model of domain interactions
  2. 1996 High

    Placed MLK3 in the MAPK hierarchy by showing it directly activates MKK4 and MKK3/6 to selectively engage JNK and p38 but not ERK, defining its core catalytic output.

    Evidence In vitro kinase assays and co-precipitation with SEK1/MKK6 in transfected cells

    PMID:8702571 PMID:9003778

    Open questions at the time
    • Did not address how MLK3 itself is activated
    • ERK linkage via B-Raf not yet known
  3. 2000 High

    Resolved the activation mechanism: Cdc42 binds the CRIB motif and drives leucine-zipper dimerization that is specifically required for MKK4 Thr258 phosphorylation and JNK activation, separating autophosphorylation from substrate targeting.

    Evidence CRIB and zipper (L410P) mutagenesis, phosphopeptide mapping, and in vitro/JNK activation assays

    PMID:10799501 PMID:10862766 PMID:9829970

    Open questions at the time
    • Cdc42 activation could not be reconstituted in vitro, implying unidentified cellular cofactors
    • Identity of the disulfide-bridge partner residues incompletely defined
  4. 2002 High

    Identified physiological agonists (ceramide, TNF-α) and mapped multiple in vivo phosphorylation sites, including Cdc42-induced Ser555/Ser556, linking upstream stimuli to defined regulatory modifications.

    Evidence In vivo/in vitro kinase assays with ceramide and sphingomyelinase; mass spectrometry and 2D phosphopeptide mapping

    PMID:11969422 PMID:12504027

    Open questions at the time
    • Functional roles of most mapped phosphosites unresolved
    • Direct ceramide-binding site not defined
  5. 2004 High

    Extended MLK3's reach to the ERK pathway by showing it is required for B-Raf activation and proliferation, positioning it upstream of B-Raf rather than as a JNK/p38-only kinase.

    Evidence RNAi silencing, phospho-B-Raf immunoblotting, and epistasis with B-Raf/Raf-1 mutant tumor lines

    PMID:15258589 PMID:15467451

    Open questions at the time
    • Whether MLK3 phosphorylates B-Raf directly not established
    • Mechanism coupling MLK3 to three distinct MAPK outputs unclear
  6. 2005 High

    Genetic ablation in mice demonstrated that MLK3's non-redundant in vivo role is selective amplification of TNF-stimulated JNK signaling.

    Evidence Mlk3−/− mouse embryonic fibroblasts with MAPK phosphorylation readouts

    PMID:15831472

    Open questions at the time
    • Redundancy with other MLK family members not directly tested
    • Tissue-specific roles not addressed
  7. 2009 High

    Defined the receptor-proximal mechanism for TNF→JNK signaling by establishing direct TRAF2–MLK3 binding via the MLK3 C-terminus as the activation step.

    Evidence Reciprocal co-IP, domain mapping, and dominant-negative TRAF2 competition

    PMID:19918265

    Open questions at the time
    • Did not resolve how TRAF2 binding triggers kinase activation
    • Scaffold organization of the complex unknown until WDR62 work
  8. 2008 High

    Revealed a kinase-independent scaffolding function: MLK3 sequesters p63RhoGEF to limit Rho activation, expanding its role from catalysis to cytoskeletal/migration control.

    Evidence Co-IP, kinase-dead rescue, Rho activity and migration assays

    PMID:18851832

    Open questions at the time
    • Structural basis of p63RhoGEF binding undefined
    • Balance between kinase and scaffold modes in vivo unclear
  9. 2010 Medium

    Identified AKT-mediated Ser674 phosphorylation as a kinase-inhibitory brake co-opted by estrogen/PI3K signaling to suppress MLK3-JNK pro-apoptotic output in breast cancer.

    Evidence Phosphosite analysis, AKT knockdown, and kinase activity assays in ER+ cells

    PMID:20145118

    Open questions at the time
    • Single-lab phosphosite mapping
    • Structural effect of Ser674 phosphorylation on the kinase domain unknown
  10. 2011 High

    Genetic epistasis established a developmental FGD1/CDC42→MLK3→ERK/p38→Runx2 axis essential for skeletal mineralization, with Mlk3 mutants phenocopying Aarskog syndrome.

    Evidence Mlk3−/− and CDC42-resistant knockin mice with phospho-MAPK and skeletal phenotyping

    PMID:21965325

    Open questions at the time
    • Direct MLK3 substrate driving Runx2 phosphorylation not pinpointed
    • Human genetic confirmation in Aarskog patients not addressed here
  11. 2012 High

    Connected MLK3 to invasion machinery by showing JNK-dependent paxillin Ser178 phosphorylation drives focal-adhesion turnover and breast cancer metastasis.

    Evidence RNAi, paxillin S178A mutant, Rho activity assay, and in vivo lung metastasis model

    PMID:22700880

    Open questions at the time
    • Relative contribution of scaffold vs kinase activity to metastasis not separated
    • Tyr118 phosphorylation mechanism not defined
  12. 2017 High

    Defined the transcriptional/proteolytic effectors of MLK3-driven invasion as FRA-1 and MMP-1/MMP-9, and described ROS- and ERK-driven positive feedback loops sustaining invasive signaling.

    Evidence RNAi/CRISPR depletion, FRA-1 rescue, invasion/transendothelial assays; in vitro ERK1 phosphorylation of kinase-dead MLK3 at Ser705/Ser758 with S705A/S758A mutants

    PMID:24894995 PMID:28604765 PMID:29084209

    Open questions at the time
    • Whether ERK-MLK3 feedback operates in non-cancer contexts unknown
    • ROS sensing mechanism upstream of MLK3 not molecularly defined
  13. 2018 Medium

    Identified additional scaffolds and effectors—WDR62 organizing TRAF2-MLK3 for TNF→JNK, and a ULK1-MLK3-ERK5 axis for antiviral gene induction—broadening MLK3's signaling repertoire.

    Evidence CRISPR/shRNA WDR62 loss-of-function with co-IP; ULK1-MLK3 co-IP with ERK5 and ISG readouts

    PMID:30091641 PMID:30459284

    Open questions at the time
    • Single-lab observations
    • Direct ULK1 phosphorylation of MLK3 not biochemically confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MLK3 dynamically partitions among its JNK, p38, ERK/B-Raf, ERK5, and scaffold-only functions, and what governs substrate selection (e.g. direct AMPKα1 Thr172 phosphorylation) in a given cellular context, remains unresolved.
  • No structural model explaining context-dependent output switching
  • Direct vs indirect substrate relationships (AMPK, B-Raf, Runx2) not fully reconstituted
  • Quantitative rules coupling input strength to JNK vs ERK choice undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 3 GO:0060090 molecular adaptor activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 1
Partners
ARHGEF25BRAFCDC42MAP2K4MAP2K6TRAF2ULK1WDR62
Complex memberships
GluR6–PSD-95–MLK3 complexTRAF2–WDR62–MLK3 complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 MLK3 directly phosphorylates and activates SEK1/MKK4 and MKK3/6 in vitro, selectively activating the SAPK/JNK and p38/RK pathways but not ERKs. Co-precipitation experiments demonstrated physical interactions between MLK3 and SEK1, and between MLK3 and MKK6. In vitro kinase assay (immunoprecipitated MLK3 phosphorylating SEK1), co-transfection, co-precipitation The EMBO journal High 8702571 9003778
1994 MLK3/SPRK/PTK1 is a serine/threonine kinase with an N-terminal SH3 domain, a kinase catalytic domain with mixed-lineage homology, tandem leucine/isoleucine zippers, a Cdc42/Rac-binding (CRIB) motif, and a proline-rich C-terminal region. Epitope-tagged SPRK autophosphorylates on serine and threonine; point mutations in the ATP-binding site abolish phosphorylation. cDNA cloning, domain analysis, in vitro kinase assay, site-directed mutagenesis of ATP-binding site The Journal of biological chemistry High 8108137 8183572 8195146
1998 MLK3 forms disulfide-bridged homodimers through its tandem leucine zipper (LZ) motif; dimerization is required for MLK3 autophosphorylation and subsequent SAPK/JNK activation. Co-expression of activated Cdc42 substantially increases MLK3 dimerization. An LZ-deletion mutant fails to activate SAPK. Co-immunoprecipitation, non-reducing SDS-PAGE, co-expression with Cdc42, dominant-negative LZ polypeptide expression The Journal of biological chemistry High 9829970
2000 Cdc42 activates MLK3/SPRK via its functional CRIB motif, altering MLK3 in vivo serine/threonine phosphorylation pattern. Unlike PAK, Cdc42-mediated activation of SPRK cannot be recapitulated in vitro with purified proteins, suggesting additional cellular components are required. Site-directed mutagenesis of CRIB motif, co-expression with activated Cdc42, comparative phosphopeptide mapping, in vitro kinase assay (negative result for recapitulation) The Journal of biological chemistry High 10799501
2000 Zipper-mediated MLK3/SPRK oligomerization is not required for Cdc42-induced autophosphorylation or histone kinase activity, but is essential for activation of JNK via MKK4. A monomeric SPRK zipper mutant (L410P) fails to phosphorylate the activating Thr258 residue of MKK4, showing that oligomerization is required for proper interaction with the downstream substrate MKK4. Site-directed mutagenesis of leucine zipper (L410P), in vitro kinase assay, JNK activation assay The Journal of biological chemistry High 10862766
2002 Ceramide and TNF-α are agonists of MLK3: a ceramide analog and bacterial sphingomyelinase activate MLK3 in vivo, and natural ceramide activates MLK3 in vitro at low nanomolar concentrations. Specific inhibition of MLK3 attenuates ceramide-induced JNK activation without affecting p38 or ERK. In vivo kinase assays, in vitro kinase assay with natural ceramide, pharmacological inhibition Molecular cell High 12504027
2002 MLK3 in vivo phosphorylation sites identified by mass spectrometry and phosphopeptide mapping include Ser524, Ser555, Ser556, Ser654, Ser705, Ser724, Ser727, Ser740, Ser758, Ser770, Ser793, and a site in Ser11-Arg37. Activated Cdc42 specifically induces phosphorylation of Ser555 and Ser556. Mass spectrometry, C18 reverse-phase HPLC, porous graphitic carbon chromatography, MALDI-MS, 2D phosphopeptide mapping, alkaline phosphatase treatment Biochemistry High 11969422
2003 Endogenous MLK3 localizes near centrosomes during interphase, disperses away transiently at G2/M, and has enhanced phosphorylation and activity during G2/M when JNK remains inactive. Overexpressed MLK3 disrupts cytoplasmic microtubules (like NIMA). MLK3 siRNA depletion increases sensitivity to taxol, indicating a role in promoting microtubule instability at M-phase entry. Immunofluorescence localization of endogenous MLK3, cell-cycle synchronization, kinase activity assays, siRNA knockdown, taxol sensitivity assay Molecular biology of the cell Medium 12529434
2004 MLK3 is required for mitogen- and cytokine-stimulated phosphorylation of B-Raf at Thr598/Ser601, a step required for B-Raf activation and downstream ERK signaling. RNAi silencing of MLK3 suppresses JNK, ERK, and p38 activation and blocks serum-stimulated cell proliferation. Tumor cells with activating B-Raf or Raf-1 mutations are unaffected by MLK3 silencing, placing MLK3 upstream of B-Raf. RNAi knockdown, phospho-specific immunoblotting, proliferation assays, genetic epistasis with B-Raf/Raf-1 mutant cell lines Nature cell biology High 15258589 15467451
2005 MLK3 deficiency in mice causes a selective reduction in TNF-stimulated JNK activation but no major defects in other MAPK signaling (ERK, p38), establishing that MLK3 contributes specifically to the TNF→JNK pathway in primary embryonic fibroblasts. Targeted gene disruption (Mlk3−/− mice), primary embryonic fibroblast stimulation, immunoblotting of MAPK phosphorylation Molecular and cellular biology High 15831472
2008 MLK3 binds directly to the Rho activator p63RhoGEF/GEFT, preventing its activation by Gαq and thereby limiting Rho activation. This scaffolding function is independent of MLK3 kinase activity and is required for cell migration. Co-immunoprecipitation, kinase-dead MLK3 rescue experiments, Rho activity assays, cell migration assays Molecular cell High 18851832
2009 TRAF2 directly interacts with MLK3 and is required for TNF-α-induced MLK3 activation. The TRAF domain of TRAF2 mediates the interaction, and the C-terminal half (aa 511–847) of MLK3 is the TRAF2-binding region. Endogenous TRAF2 and MLK3 associate in a TNF-α time-dependent manner; competition with a TRAF2 deletion mutant attenuates MLK3 kinase activity and downstream JNK activation. Co-immunoprecipitation, domain mapping, kinase activity assays, dominant-negative TRAF2 competition Cell research High 19918265
2010 AKT1/2 phosphorylates MLK3 at Ser674, which inhibits MLK3 kinase activity in ER+ breast cancer cells. Estrogen (E2) activates AKT via ERα-PI3K interaction, leading to MLK3 Ser674 phosphorylation and suppression of MLK3-JNK pro-apoptotic signaling. Site-directed phosphorylation site analysis, AKT knockdown, kinase activity assays, immunoblotting Cancer research Medium 20145118
2011 MLK3 functions downstream of FGD1/CDC42 in osteoblasts to regulate ERK and p38 MAPK, which phosphorylate Runx2 to control osteoblast differentiation. Mlk3−/− mice display skeletal defects mirroring Aarskog syndrome; a CDC42-resistant MLK3 knockin allele produces the same defects, demonstrating that CDC42 activation of MLK3 is specifically required for skeletal mineralization. Targeted gene disruption (Mlk3−/−), knockin of CDC42-resistant Mlk3 allele, phospho-MAPK immunoblotting, skeletal phenotype analysis The Journal of clinical investigation High 21965325
2012 MLK3 promotes phosphorylation of the focal adhesion scaffold paxillin at Ser178 (via JNK) and Tyr118, limiting Rho activity to promote focal adhesion turnover and cell migration. MLK3 silencing increases focal adhesions and stress fibers, and reduces breast cancer lung metastasis in vivo. RNAi knockdown, pharmacological inhibition, paxillin S178A mutant expression, Rho activity assay, in vivo metastasis model Cancer research High 22700880
2013 MLK3 promotes saturated fatty acid-induced JNK activation in macrophages in vitro and in vivo. MLK3-deficient mice on high-fat diet show decreased adiposity, attenuated JNK activation, reduced macrophage infiltration, and improved insulin resistance, demonstrating MLK3's role in diet-induced metabolic dysfunction. MLK3 knockout mice, high-fat diet model, JNK activation assays, macrophage polarization, in vitro palmitate stimulation American journal of physiology. Endocrinology and metabolism High 23860122
2010 GSK-3β inactivation disrupts MLK3 dimerization-induced autophosphorylation in microglia, blocking the MLK3→MKK4→JNK signaling cascade and reducing LPS-induced TNF-α production. Co-immunoprecipitation demonstrated a functional interaction between MLK3 and GSK-3β. Co-immunoprecipitation, GSK-3β inhibitors and siRNA, ELISA, western blotting, NF-κB reporter assay Journal of neuroinflammation Medium 21194439
2014 MLK3 is part of a positive feedback loop with ERK and JNK: low ROS preferentially activates ERK while high ROS activates JNK via MLK3. MLK3 knockdown or inhibition shifts ROS-induced responses toward ERK activation and reduces cell death, establishing MLK3 as a critical switch between proliferative and apoptotic ROS responses. Mathematical modeling, MLK3 knockdown, MLK3 inhibitor, phospho-ERK/JNK immunoblotting, cell viability assays Science signaling Medium 24894995
2017 MLK3 phosphorylation by ERK1/2 at Ser705 and Ser758 promotes MLK3-dependent B-Raf and ERK1/2 activation, creating a positive feedback loop that enhances oxidative stress-induced colorectal cancer cell invasion. Active ERK1 phosphorylates kinase-dead MLK3 in vitro; the S705A/S758A mutant shows reduced ERK1/2 activation and decreased interaction with B-Raf. In vitro kinase assay (ERK1 phosphorylating kinase-dead MLK3), co-immunoprecipitation, site-directed mutagenesis (S705A/S758A), invasion assay, siRNA knockdown Oncogene High 29084209
2018 IFN-γ receptor stimulation activates ULK1, which interacts with MLK3 and is required for MLK3 phosphorylation and downstream ERK5 activation. This ULK1-MLK3-ERK5 axis promotes transcription of antiviral IFN-stimulated genes independently of ULK1's autophagy function. Co-immunoprecipitation (ULK1-MLK3 interaction), phosphorylation assays, ERK5 activation assays, IFN-stimulated gene expression Science signaling Medium 30459284
2015 HER2 suppresses MLK3 kinase activity in HER2+ breast cancer via AKT-mediated phosphorylation of MLK3 at Ser674. HER2 depletion or treatment with trastuzumab/lapatinib stimulates MLK3 activity; PI3K/AKT inhibitors block this effect. MLK3 knockdown blunts pro-apoptotic effects of HER2-targeted therapies. Kinase activity assays in HER2+ tumor tissues and cell lines, HER2/HER3 siRNA, trastuzumab/lapatinib treatment, PI3K/AKT inhibition, MLK3 stable knockdown The Journal of biological chemistry Medium 26152725
2015 MLK3 directly phosphorylates AMPKα1 at Thr172 independently of LKB1. GST pull-down assays demonstrate direct interaction between AMPKα1 and MLK3. MLK3-mediated AMPK phosphorylation is AMP-independent. In vitro kinase assay, GST pull-down, LKB1-deficient cell lines, AMPK phosphorylation at T172 PloS one Medium 25874865
2017 MLK3 drives invasion through upregulation of the oncogenic transcription factor FRA-1 and matrix metalloproteinases MMP-1 and MMP-9. MLK3 depletion (siRNA or CRISPR/Cas9) reduces FRA-1, MMP-1, and MMP-9 levels in TNBC cells. MLK3 controls transendothelial migration via tumor cell-derived MMP-1. RNAi knockdown, CRISPR/Cas9 editing, FRA-1 siRNA rescue, invasion assay, transendothelial migration assay, circulating tumor cell analysis Oncogenesis High 28604765
2017 MLK3 promotes GBM cell migration and invasion downstream of EGFR via a DOCK180→RAC1→MLK3→JNK signaling axis. DOCK180 (a RAC1 GEF overexpressed in invasive GBM) activates MLK3-JNK in a RAC1-dependent manner. MLK3 silencing or MLK inhibition blocks EGF-induced JNK activation and cell invasion. RNAi knockdown of MLK3 and DOCK180, MLK inhibitor, JNK activation assays, migration/invasion assays, RAC1 dependence assessed Molecular cancer research Medium 28487380
2018 WDR62 scaffolds TRAF2 and MLK3 to mediate TNF-α-dependent JNK activation. CRISPR/Cas9 and shRNA-mediated WDR62 loss of function reduces TNF-α-induced JNK activation and increases resistance to TNF-α-induced cell death. CRISPR/Cas9 knockout, shRNA knockdown, co-immunoprecipitation (TRAF2-WDR62-MLK3 interaction), JNK activation assay Molecular biology of the cell Medium 30091641
2005 In rat hippocampus during cerebral ischemia, PSD-95 physically links GluR6 (kainate receptor) to MLK3 via its SH3 domain, forming a GluR6•PSD-95•MLK3 signaling module that activates MLK3 autophosphorylation and subsequent JNK3 activation. Co-immunoprecipitation, immunoblotting, antisense oligodeoxynucleotide knockdown of PSD-95, GluR6 antagonists Brain research Medium 16256962
2001 MLK-3 is involved in HTLV-1 Tax-mediated NF-κB activation; Tax induces MLK-3 expression, and MLK-3 functionally contributes to Tax-driven NF-κB signaling. cDNA microarray, functional NF-κB signaling assays Oncogene Low 11494144
2006 Akt inhibits the MLK3/JNK3 pathway by phosphorylating Rac1 at Ser71, inactivating Rac1 and thereby preventing MLK3 autophosphorylation. Co-immunoprecipitation revealed that Akt physically interacts with Rac1 in the hippocampal CA1 region. Co-immunoprecipitation (Akt-Rac1), tyrosine phosphatase inhibition, immunoblotting of MLK3/MKK7/JNK3 phosphorylation Journal of neurochemistry Medium 16831194
2014 MLK3 regulates fMLP-stimulated neutrophil motility: genetic (Mlk3−/− mice) or pharmacological (URMC099 inhibitor) MLK3 inhibition blocks fMLP-induced chemotaxis, random motility, and F-actin formation in vitro, and reduces fMLP-induced peritoneal neutrophil recruitment in vivo. Mlk3−/− mice, pharmacological inhibitor (URMC099), in vitro chemotaxis, F-actin formation assay, in vivo peritoneal recruitment Molecular immunology Medium 24389043

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6. The EMBO journal 281 9003778
1996 The mixed lineage kinase SPRK phosphorylates and activates the stress-activated protein kinase activator, SEK-1. The Journal of biological chemistry 211 8702571
1981 Structural polarity of kinetochore microtubules in PtK1 cells. The Journal of cell biology 192 7251657
2020 Pyroptosis and ferroptosis induced by mixed lineage kinase 3 (MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload. Cell death & disease 182 32710001
1997 Kinetochore fiber maturation in PtK1 cells and its implications for the mechanisms of chromosome congression and anaphase onset. The Journal of cell biology 174 9199171
2015 MAP3K11/GDF15 axis is a critical driver of cancer cachexia. Journal of cachexia, sarcopenia and muscle 167 27239403
2004 MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation. Nature cell biology 146 15258589
1991 PtK1 cells contain a nondiffusible, dominant factor that makes the Golgi apparatus resistant to brefeldin A. The Journal of cell biology 127 1710224
1998 Dimerization via tandem leucine zippers is essential for the activation of the mitogen-activated protein kinase kinase kinase, MLK-3. The Journal of biological chemistry 121 9829970
2005 Role of MLK3 in the regulation of mitogen-activated protein kinase signaling cascades. Molecular and cellular biology 111 15831472
1994 Identification and characterization of SPRK, a novel src-homology 3 domain-containing proline-rich kinase with serine/threonine kinase activity. The Journal of biological chemistry 110 8195146
1985 Alteration of intermediate filament distribution in PtK1 cells by acrylamide. European journal of cell biology 102 2411559
2010 Glycogen synthase kinase-3β inactivation inhibits tumor necrosis factor-α production in microglia by modulating nuclear factor κB and MLK3/JNK signaling cascades. Journal of neuroinflammation 101 21194439
2013 miR-138 protects cardiomyocytes from hypoxia-induced apoptosis via MLK3/JNK/c-jun pathway. Biochemical and biophysical research communications 94 24211202
2001 Genome-wide expression changes induced by HTLV-1 Tax: evidence for MLK-3 mixed lineage kinase involvement in Tax-mediated NF-kappaB activation. Oncogene 89 11494144
2002 Activation of the Drosophila MLK by ceramide reveals TNF-alpha and ceramide as agonists of mammalian MLK3. Molecular cell 87 12504027
1994 MLK-3: identification of a widely-expressed protein kinase bearing an SH3 domain and a leucine zipper-basic region domain. Oncogene 86 8183572
2004 Mixed lineage kinase 3 (MLK3)-activated p38 MAP kinase mediates transforming growth factor-beta-induced apoptosis in hepatoma cells. The Journal of biological chemistry 80 15069087
2000 Cdc42-induced activation of the mixed-lineage kinase SPRK in vivo. Requirement of the Cdc42/Rac interactive binding motif and changes in phosphorylation. The Journal of biological chemistry 78 10799501
2001 PTK1, a mitogen-activated-protein kinase gene, is required for conidiation, appressorium formation, and pathogenicity of Pyrenophora teres on barley. Molecular plant-microbe interactions : MPMI 76 11204774
1983 A microtubule-associated protein antigen unique to mitotic spindle microtubules in PtK1 cells. The Journal of cell biology 75 6339516
2012 MLK3 regulates paxillin phosphorylation in chemokine-mediated breast cancer cell migration and invasion to drive metastasis. Cancer research 74 22700880
1993 Structure of the colcemid-treated PtK1 kinetochore outer plate as determined by high voltage electron microscopic tomography. The Journal of cell biology 73 8421050
1998 Guanine-nucleotide exchange protein C3G activates JNK1 by a ras-independent mechanism. JNK1 activation inhibited by kinase negative forms of MLK3 and DLK mixed lineage kinases. The Journal of biological chemistry 65 9430657
1981 A permeabilized cell model for studying cell division: a comparison of anaphase chromosome movement and cleavage furrow constriction in lysed PtK1 cells. The Journal of cell biology 61 6111566
2010 MLK3 is critical for breast cancer cell migration and promotes a malignant phenotype in mammary epithelial cells. Oncogene 59 20514022
1999 The JNK/SAPK activator mixed lineage kinase 3 (MLK3) transforms NIH 3T3 cells in a MEK-dependent fashion. Cancer research 57 10232608
2013 Connective tissue growth factor induces collagen I expression in human lung fibroblasts through the Rac1/MLK3/JNK/AP-1 pathway. Biochimica et biophysica acta 54 23906792
1986 Alteration of the distribution of intermediate filaments in PtK1 cells by acrylamide. II: Effect on the organization of cytoplasmic organelles. Cell motility and the cytoskeleton 54 3698106
2019 MiR-199a-5p suppresses non-small cell lung cancer via targeting MAP3K11. Journal of Cancer 53 31258753
2017 MLK3 phosphorylation by ERK1/2 is required for oxidative stress-induced invasion of colorectal cancer cells. Oncogene 53 29084209
2014 MLK3 is part of a feedback mechanism that regulates different cellular responses to reactive oxygen species. Science signaling 53 24894995
2005 The neuroprotective effects of K252a through inhibiting MLK3/MKK7/JNK3 signaling pathway on ischemic brain injury in rat hippocampal CA1 region. Neuroscience 53 15680699
2011 MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice. The Journal of clinical investigation 52 21965325
1994 PTK1, a novel protein kinase required for proliferation of human melanocytes. Oncogene 51 8108137
1993 Three-dimensional organization of the ribosomal genes and Ag-NOR proteins during interphase and mitosis in PtK1 cells studied by confocal microscopy. Chromosoma 49 7681367
2017 MLK3 regulates FRA-1 and MMPs to drive invasion and transendothelial migration in triple-negative breast cancer cells. Oncogenesis 46 28604765
2000 Zipper-mediated oligomerization of the mixed lineage kinase SPRK/MLK-3 is not required for its activation by the GTPase cdc 42 but Is necessary for its activation of the JNK pathway. Monomeric SPRK L410P does not catalyze the activating phosphorylation of Thr258 of murine MITOGEN-ACTIVATED protein kinase kinase 4. The Journal of biological chemistry 45 10862766
2006 Akt inhibits MLK3/JNK3 signaling by inactivating Rac1: a protective mechanism against ischemic brain injury. Journal of neurochemistry 44 16831194
2017 A novel lnc-PCF promotes the proliferation of TGF-β1-activated epithelial cells by targeting miR-344a-5p to regulate map3k11 in pulmonary fibrosis. Cell death & disease 42 29072702
2003 A new identity for MLK3 as an NIMA-related, cell cycle-regulated kinase that is localized near centrosomes and influences microtubule organization. Molecular biology of the cell 42 12529434
1998 Relevance of kinetochore size and microtubule-binding capacity for stable chromosome attachment during mitosis in PtK1 cells. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 42 9543015
2005 Activation of c-Jun NH2-terminal kinase 3 is mediated by the GluR6.PSD-95.MLK3 signaling module following cerebral ischemia in rat hippocampus. Brain research 41 16256962
2008 MLK3 limits activated Galphaq signaling to Rho by binding to p63RhoGEF. Molecular cell 40 18851832
2014 MLK3 promotes melanoma proliferation and invasion and is a target of microRNA-125b. Clinical and experimental dermatology 39 24635082
2005 Knock-down of POSH expression is neuroprotective through down-regulating activation of the MLK3-MKK4-JNK pathway following cerebral ischaemia in the rat hippocampal CA1 subfield. Journal of neurochemistry 39 16248889
1989 Three-dimensional organization of micronuclei induced by colchicine in PtK1 cells. Experimental cell research 39 2917606
1987 Primary cilia cycle in PtK1 cells: effects of colcemid and taxol on cilia formation and resorption. Cell motility and the cytoskeleton 39 2885096
2013 Dynamic bonds and polar ejection force distribution explain kinetochore oscillations in PtK1 cells. The Journal of cell biology 38 23671311
2013 MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet. American journal of physiology. Endocrinology and metabolism 38 23860122
2020 Hederagenin Attenuates Cerebral Ischaemia/Reperfusion Injury by Regulating MLK3 Signalling. Frontiers in pharmacology 37 32848779
2006 Inhibition of MLK3-MKK4/7-JNK1/2 pathway by Akt1 in exogenous estrogen-induced neuroprotection against transient global cerebral ischemia by a non-genomic mechanism in male rats. Journal of neurochemistry 37 17064355
1986 Preservation of chromosome integrity during micronucleation induced by colchicine in PtK1 cells. Chromosoma 37 3549194
2016 MLK3 Signaling in Cancer Invasion. Cancers 36 27213454
2012 HBx activates FasL and mediates HepG2 cell apoptosis through MLK3-MKK7-JNKs signal module. World journal of gastroenterology 34 22509080
2002 Identification of in vivo phosphorylation sites of MLK3 by mass spectrometry and phosphopeptide mapping. Biochemistry 33 11969422
2004 A novel role for mixed lineage kinase 3 (MLK3) in B-Raf activation and cell proliferation. Cell cycle (Georgetown, Tex.) 30 15467451
1992 Specific types of prosomes are associated to subnetworks of the intermediate filaments in PtK1 cells. European journal of cell biology 30 1281772
2009 Coactivation of GABA receptors inhibits the JNK3 apoptotic pathway via disassembly of GluR6-PSD-95-MLK3 signaling module in KA-induced seizure. Epilepsia 29 19694794
1981 Effect of hypothermia (20-25 degrees C) on mitosis in PtK1 cells. Cell biology international reports 29 7249090
2020 MiR-199a-3p/5p participated in TGF-β and EGF induced EMT by targeting DUSP5/MAP3K11 in pterygium. Journal of translational medicine 28 32867783
2017 EGFR Signals through a DOCK180-MLK3 Axis to Drive Glioblastoma Cell Invasion. Molecular cancer research : MCR 28 28487380
2015 Decrement of miR-199a-5p contributes to the tumorigenesis of bladder urothelial carcinoma by regulating MLK3/NF-κB pathway. American journal of translational research 28 26885275
2014 MLK3-MKK3/6-P38MAPK cascades following N-methyl-D-aspartate receptor activation contributes to amyloid-β peptide-induced apoptosis in SH-SY5Y cells. Journal of neuroscience research 28 24482239
2019 Suppression of the RAC1/MLK3/p38 Signaling Pathway by β-Elemene Alleviates Sepsis-Associated Encephalopathy in Mice. Frontiers in neuroscience 27 31068775
2010 Estrogen suppresses MLK3-mediated apoptosis sensitivity in ER+ breast cancer cells. Cancer research 27 20145118
2000 Length control of primary cilia: analysis of monociliate and multiciliate PtK1 cells. Biology of the cell 27 11374436
2009 TRAF2-MLK3 interaction is essential for TNF-alpha-induced MLK3 activation. Cell research 26 19918265
2008 Co-activation of GABA receptors inhibits the JNK3 apoptotic pathway via the disassembly of the GluR6-PSD95-MLK3 signaling module in cerebral ischemic-reperfusion. FEBS letters 25 18307989
2006 Decreased polarity and increased random motility in PtK1 epithelial cells correlate with inhibition of endosomal recycling. Journal of cell science 25 16931597
2006 Down-regulation Cdc42 attenuates neuronal apoptosis through inhibiting MLK3/JNK3 cascade during ischemic reperfusion in rat hippocampus. Cellular signalling 25 17161586
1988 Acrylamide treatment of PtK1 cells causes dephosphorylation of keratin polypeptides. Cell motility and the cytoskeleton 25 2463103
2018 IFN-γ-inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5. Science signaling 24 30459284
2004 Postsynaptic density protein 95 antisense oligodeoxynucleotides inhibits the activation of MLK3 and JNK3 via the GluR6.PSD-95.MLK3 signaling module after transient cerebral ischemia in rat hippocampus. Neuroscience letters 24 15308300
2016 Overexpression of miR-199a-5p decreases esophageal cancer cell proliferation through repression of mitogen-activated protein kinase kinase kinase-11 (MAP3K11). Oncotarget 23 26717044
2015 MAP3K11 is a tumor suppressor targeted by the oncomiR miR-125b in early B cells. Cell death and differentiation 22 26138442
1995 Cytochalasin J affects chromosome congression and spindle microtubule organization in PtK1 cells. Cell motility and the cytoskeleton 22 8608604
1984 Dynamics of keratin filaments and the intermediate filament distribution center during shape change in PtK1 cells. Cell motility 22 6204764
2014 MLK3 regulates fMLP-stimulated neutrophil motility. Molecular immunology 21 24389043
2006 Antioxidant N-acetylcysteine inhibits the activation of JNK3 mediated by the GluR6-PSD95-MLK3 signaling module during cerebral ischemia in rat hippocampus. Neuroscience letters 21 17030433
2009 Aneuploidy in mitosis of PtK1 cells is generated by random loss and nondisjunction of individual chromosomes. Journal of cell science 20 19737818
1983 Nocodazole pretreatment in anaphase selectively reduces anaphase B in PtK1 cells. Cell motility 20 6850812
2022 Circular RNA ACTA1 Acts as a Sponge for miR-199a-5p and miR-433 to Regulate Bovine Myoblast Development through the MAP3K11/MAP2K7/JNK Pathway. Journal of agricultural and food chemistry 19 35234473
2016 Heme Oxygenase-1 Inhibits Neuronal Apoptosis in Spinal Cord Injury through Down-Regulation of Cdc42-MLK3-MKK7-JNK3 Axis. Journal of neurotrauma 19 27526795
2015 MLK3 phophorylates AMPK independently of LKB1. PloS one 19 25874865
2015 Human Epidermal Growth Factor Receptor 2 (HER2) Impedes MLK3 Kinase Activity to Support Breast Cancer Cell Survival. The Journal of biological chemistry 19 26152725
2008 Neuroprotection of hypothermia against neuronal death in rat hippocampus through inhibiting the increased assembly of GluR6-PSD95-MLK3 signaling module induced by cerebral ischemia/reperfusion. Hippocampus 19 18172894
2001 Role of MLK3-mediated activation of p70 S6 kinase in Rac1 transformation. The Journal of biological chemistry 19 11713255
1987 Cytochalasin B-induced redistribution of cytokeratin filaments in PtK1 cells. Cell motility and the cytoskeleton 19 2440591
2018 The potential role of HO-1 in regulating the MLK3-MKK7-JNK3 module scaffolded by JIP1 during cerebral ischemia/reperfusion in rats. Behavioural brain research 18 30412737
1988 Calmodulin colocalization with cold-stable and nocodazole-stable microtubules in living PtK1 cells. European journal of cell biology 18 3068060
2022 The role of mixed lineage kinase 3 (MLK3) in cancers. Pharmacology & therapeutics 17 36038020
2018 miR-140-5p aggravates hypoxia-induced cell injury via regulating MLK3 in H9c2 cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 17 29864954
2018 WDR62 mediates TNFα-dependent JNK activation via TRAF2-MLK3 axis. Molecular biology of the cell 17 30091641
2016 Hepatitis B Virus X Protein Modulates Apoptosis in NRK-52E Cells and Activates Fas/FasL Through the MLK3-MKK7-JNK3 Signaling Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 17 27606894
1987 RNA polymerase activity in PtK1 micronuclei containing individual chromosomes. An in vitro and in situ study. Experimental cell research 17 3817015
1985 Cellular compartments in mitotic cells: ultrahistochemical identification of Golgi elements in PtK-1 cells. Biology of the cell 17 3159452
1984 Sucrose-induced spindle elongation in mitotic PtK-1 cells. European journal of cell biology 17 6489361
2018 miRNA-138 regulates MLK3/JNK/MAPK pathway to protect BV-2 cells from H2O2-induced apoptosis. Bratislavske lekarske listy 16 29749242
2017 Heme oxygenase-1 protects spinal cord neurons from hydrogen peroxide-induced apoptosis via suppression of Cdc42/MLK3/MKK7/JNK3 signaling. Apoptosis : an international journal on programmed cell death 16 27864650

Missed literature

Know a paper Affinage missed for MAP3K11? Flag it for the maintainers and the community.

No submissions yet.